There is general recognition that intracellular calcium (Ca2+) plays an important role in many biological processes such as gene regulation, memory, and cell death. See Muth, J. N. et al. Trends Pharmacol Sci 22, 526-32 (2001); and Carafoli, E. et al. Crit Rev Biochem Mol Biol 36, 107-260 (2001).
More specifically, there have been reports that abnormal levels of intracellular Ca2+ foster inappropriate calcium homeostasis in a variety of cells, tissues and organs. Cardiac and neural tissue are thought to be especially sensitive to calcium. As an illustration, certain neurons are believed to undergo abnormal neurotransmitter release, dendritic Ca2+ transients and Ca2+ action potentials in the presence of inadequate calcium homeostasis.
Many disorders are thought to arise or be exacerbated by inappropriate calcium homeostasis, particularly those impacting the central (CNS) and peripheral (PNS) nervous systems, as well as the endocrine and cardiovascular systems.
Voltage-gated calcium channels are thought to help control the intracellular flow of Ca2+. These channels (also known as voltage-dependent calcium channels or VDCCs) have been disclosed as being a heterogeneous class of proteins that are responsive to depolarization. The conversion of the intracellular calcium flow by these and other channel proteins is thought to impact a wide spectrum of biological responses. See generally Catterall, W. A. Ann. Rev. Cell Dev. 16: 521 (2000) and U.S. Pat. No. 5,436,128.
Nearly all calcium channels are categorized as T, L, N, P, and Q types. These designations are based largely on electrophysiological and pharmacological properties of the channels. See Catterall, supra; and Dunlap, K. et al. Trends Neurosci. 18:89 (1995).
By way of example, L-type calcium channels are believed to be sensitive to dihydropyridine (DHP) agonists and antagonists as well as certain other compounds. The structure and function of these calcium channels have been disclosed at the molecular level. See eg., Catterall, supra; U.S. Pat. Nos. 6,365,337; U.S. Pat. Publication No. 2002009772; Perez-Reyes, E. et al. J. Biol. Chem. 267: 1792 (1991); and references cited therein.
See also Ertel, E. A et al. in Neuron 25: 533 (2000) (disclosing various voltage-gated calcium channels with reference to the molecular structure and function of these proteins).
There have been attempts to understand how L-type and other calcium channels are regulated. In this regard, a link between Ca2+ channel trafficking and certain guanosine triphosphatase enzymes (GTPases) has been reported. More specifically, interaction between some Ca2+ channel subunits and a ras-like GTPase called Gem (also called Kir/Gem) has been disclosed.
The structure and function of Gem has been reported. See Maguire, J. et al. Science 265: 241 (1994) (disclosing the molecular structure of murine and human Gem proteins, for instance). It has been proposed that Gem helps prevent β subunit-mediated trafficking of Ca2+ channels under appropriate conditions.
There is almost universal belief that the heart maintains an intrinsic rhythm by creating electric stimuli. This leads to contraction of the myocardium. These contractions are the engine that moves blood throughout the vascular system. See generally The Heart and Cardiovascular System. Scientific Foundations. (1986) (Fozzard, H. A. et al. eds) Raven Press, NY.
Certain channel proteins are thought to be closely linked to normal heart function. For instance, genetic mutation of some channel proteins may facilitate or at least aggravate heart disorders such as arrhythmias. As a group, such heart disorders have been referred to as “channelopathies” to denote relationship with abnormal channel protein function. See Marban, E. Nature 415: 213 (2002).
Abnormal channel proteins are thought to impact other heart disorders including hypertrophy, apoptosis, remodeling, fibrillation, angina and in some cases infarcts (“heart attack”). See Bers, D. M. Nature 415, 198-205 (2002); and Marban, E. supra.
There have been attempts to control the activity of certain channel proteins as a means of preventing, treating or at least reducing the severity of some heart disorders.
For instance, several synthetic Ca2+ channel blocking drugs (also referred to as “Ca2+ channel blockers”) have been approved for use. Some Ca2+ channel blockers are thought to impact the atrioventricular (AV) node of the heart preferentially. These agents are sometimes referred to as “AV nodal blocking” agents or like phrase. See generally Robertson, M. and D. Robertson in Goodman & Gilman's The Pharmacological Basis of Therapeutics 9th Ed. Hardman, J. G et al. Eds. (1996) Chapters 32-35, pp. 759-800 and references cited therein.
The L-type calcium channel has been reported to be a specific target for some calcium channel blockers. See Feron, O. et al. Br J Pharmacol 118, 659-64. (1996); and Kurita, Y. et al. Cardiovasc Res 54, 447-55. (2002).
However, there are reports that therapeutic use of many Ca2+ channel blockers is associated with potentially life-threatening side-effects. These include hypotension, constipation, and heart block. See Missiaen, L. et al. Cell Calcium 28, 1-21 (2000); and Robertson, M., supra for a review of these and other shortcomings associated with the medical use of Ca2+ channel blockers.
Gene therapy has been proposed as a means to prevent or treat certain heart disorders. See Marban, E. supra; Miake, J. et al. Nature 419: 132; Marban, E. et al. Cold Spring Harbor Symp. Quant. Biol. Vol. LXVII: 527 (2002); and Miake, J. et al. J. Clin. Invest. 111: 1529 (2003); and references cited therein.
It would be desirable to have an invention that can modulate calcium channels within a pre-determined region of interest. Preferably, the invention would focally deliver a specific therapeutic composition to the region and reduce or eliminate potential for non-specific channel modulation outside that region. It would be especially desirable to have an invention that does not require use of a calcium channel blocker to modulate the calcium channel focally and within the region of interest.